Song Li, He Yijing, Ou Jiayao, Zhao Yongbo, Li Ruoyu, Cheng Jingjing, Lin Chin-Hsien, Ho Margaret S
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai 200092, China.
Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin-Cun Road, Shanghai 200065, China.
Cell Rep. 2017 Jan 31;18(5):1132-1143. doi: 10.1016/j.celrep.2017.01.005.
Parkinson's disease (PD) is a common neurodegenerative disorder that exhibits motor and non-motor symptoms, as well as pathological hallmarks, including dopaminergic (DA) neuron death and formation of α-synuclein (α-Syn) Lewy bodies. Cyclin-G-associated kinase (GAK), a PD susceptibility gene identified through genome-wide association studies (GWAS), is a ubiquitous serine/threonine kinase involved in clathrin uncoating, though its PD-related function remains elusive. Here, we implicate the Drosophila GAK homolog, auxilin (aux), in a broad spectrum of parkinsonian-like symptoms. Downregulating aux expression leads to progressive loss of climbing ability, decreased lifespan, and age-dependent DA neuron death similar to α-Syn overexpression. Reduced aux expression further enhances and accelerates α-Syn-mediated DA neuron loss. Flies with reduced aux expression are more sensitive to the toxin paraquat, suggesting that genetic and environmental factors intertwine. Taken together, these findings decipher a pivotal role for GAK/aux and suggest mechanisms underlying PD.
帕金森病（PD）是一种常见的神经退行性疾病，表现出运动和非运动症状以及病理特征，包括多巴胺能（DA）神经元死亡和α-突触核蛋白（α-Syn）路易小体的形成。细胞周期蛋白G相关激酶（GAK）是一种通过全基因组关联研究（GWAS）鉴定出的PD易感基因，是一种普遍存在的丝氨酸/苏氨酸激酶，参与网格蛋白脱衣被，但其与PD相关的功能仍不清楚。在这里，我们发现果蝇GAK同源物辅助蛋白（aux）与广泛的帕金森样症状有关。下调aux表达会导致攀爬能力逐渐丧失、寿命缩短以及与α-Syn过表达类似的年龄依赖性DA神经元死亡。aux表达降低会进一步增强和加速α-Syn介导的DA神经元损失。aux表达降低的果蝇对百草枯毒素更敏感，这表明遗传和环境因素相互交织。综上所述，这些发现揭示了GAK/aux的关键作用，并提示了PD的潜在机制。
